Pharmaceutical Excipients

A Business Unit of Hercules Incorporated

Table of Contents
Introduction ............................................................................................. 1

Pharmaceutical Applications Tablet Binder .......................................................................................... 2 Modified Release ................................................................................... 4 Liquid and Semi-Solid Formulations....................................................... 8 Tablet Coating ........................................................................................ 9

Aqualon Products KLUCEL hydroxypropylcellulose (HPC) .............................................. 10 AQUALON and BLANOSE sodium carboxymethylcellulose (CMC) .... 12 AQUALON ethylcellulose (EC)............................................................ 14 NATROSOL hydroxyethylcellulose (HEC) ........................................... 16

Delivering Pharmaceutical Performance Aqualon has been delivering pharmaceutical performance since the 1950s. through the legacy of Hercules Incorporated and Henkel GmBH. Aqualon was originally founded in 1987 as a joint venture between the water-soluble polymer groups of these two companies. In 1989, Aqualon became a business unit of Hercules Incorporated.

Aqualon...A World Leader in Products That Manage the Physical Properties of Aqueous Systems
Functions Tablet Binding Power Thickening and Rheology Control Film Formation Water Retention Adhesive Strength Suspending and Emulsifying

Markets Pharmaceuticals Personal Care Water-Based Paints Construction Materials Food Paper Mills Printing Inks Aviation Fluids Oil and Gas Exploration

Pharmaceutical Excipients KLUCEL hydroxypropylcellulose (HPC) Tablet binding, modified release, film coating NATROSOL hydroxyethylcellulose (HEC) Modified release, film coating, solution/suspension rheology AQUALON and BLANOSE sodium carboxymethylcellulose (CMC) Solution/suspension rheology, tablet coating, modified release, film forming AQUALON ethylcellulose (EC) Modified release, microencapsulation, tablet coating and binding, flavor masking

Production Facilities Alizay, France Hopewell, Virginia, U.S.A. Zwijndrecht, the Netherlands

Headquarters, Corporate Research Center, and Pharmaceutical Laboratory Wilmington, Delaware, U.S.A.

For further information, including samples, technical literature, and sales information: Visit our website at www.aqualon.com. Contact any of the offices listed in this publication.

Tablet Binder
KLUCEL hydroxypropylcellulose (HPC) provides premier performance as a tablet binder. KLUCEL exhibits a unique combination of thermoplasticity with organic solvent or aqueous solubility, allowing tough tablet preparation using many different formulation techniques. Unmatched tablet hardness and friability are found with low viscosity grades of KLUCEL, at typical use levels of 2 to 8%, in a wide variety of processing options Wet Granulation (high or low shear or fluid bed): Grades EF and LF with regular particle size are often used in granulating solutions. Alternately, grade EXF, with fine particle size, can be added dry to other ingredients, followed by granulation with water or solvent. Direct Compression or Dry Granulation (roller compaction or slugging): Grade EXF with fine particle size is recommended. Beyond unmatched tablet hardness and friability, benefits of tableting with KLUCEL include: Reduction or elimination of tablet capping; Smaller tablet size and production efficiency; and Lower compression and ejection forces. Thermoplastic Properties The benefits of KLUCEL as a tough tablet binder are well known. In pure tablet compacts, the high energy absorption and ductility of KLUCEL is shown in Figure 1 versus other binders and fillers. (References A and B.)
Stress, N 250 8 200 6 150 100 50 0 0 1 2 Strain, mm Figure 1: Pure Compacts Under Compression 3 4 KLUCEL EXF HPC PVP MC PGS 0 0 10 20 Compression Force, kN Figure 3: Low Shear Wet Granulation Tablets 4 2

High Tablet Hardness and Low Friability The thermoplasticity of KLUCEL allows production of tough tablets. Figures 2 through 5 demonstrate the binder performance of KLUCEL in comparison studies utilizing low shear and fluid bed granulation of tablets formulated with 83.3% poorly-compressible acetaminophen. These high dose studies show KLUCEL can be used at lower use levels to yield superior tablets, compared to tablets with higher binders levels of HPMC, MC, PVP and pregelatinized starch (PGS). High-dose acetaminophen formulations using lower levels of these poorer binders were simply poor, due to capping. Aqualon has found similar comparative results with other drug compounds. (References C, D, E, and F.)
Crushing Force, N 200 160

4% HPC 8% MC 8% HPMC

120

80 40 0 0 5

8% PVP

12% PGS

10 15 20 25 30

Compression Force, kN Figure 2: Low Shear Wet Granulation Tablets

Friability, % 10

4% HPC 8% MC 8% HPMC

30

Tablet Binder
80% Dissolution Time, min 30 25 20 15 10 5 0 Selected references on tablet binding are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. A. Effects of Binder Toughness and Flowability on Pharmaceutical Tablet Performance (Aqualon Pharmaceutical Technology Report PTR-015) B. Correlating the Ejection Force of Tablets with the Toughness of Binders in the Solid Dosage Forms (Aqualon Pharmaceutical Technology Report PTR-009) C. Evaluation of Low-Viscosity Polymers in a Model High-Dose, Acetaminophen Formulation (Aqualon Pharmaceutical Technology Report PTR-011) D. Effect of KLUCEL EF and EXF Hydroxypropylcellulose as Granulating Agents in Low-Dose Hydrochlorothiazide Tablet Formulation (Aqualon Technical Information Bulletin VC-572A) E. Validation of Tablet Dissolution Method by High Performance Liquid Chromatography (Aqualon Pharmaceutical Technology Report PTR-006) F. An Evaluation of Fluidized Bed Granulation Methods for Preparing Tablets of a High-Dose, Poorly-Compactible Drug (Aqualon Pharmaceutical Technology Report PTR-010) G. Lot-to-Lot Uniformity of KLUCEL EXF Hydroxypropylcellulose as a Granulating Agent (Aqualon Technical Information Bulletin VC-588A) H. Assessment of Low-Viscosity Polymers as Direct Compression Binders in a Model System (Aqualon Pharmaceutical Technology Report PTR-005-1) I. G.W. Skinner et al, Drug Dev Ind Pharm 1999 Oct; 25(10):1121-8; The evaluation of fine-particle hydroxypropylcellulose as a roller compaction binder in pharmaceutical applications

4% HPC

8% MC

8% HPMC

8% PVP

12% PGS

Figure 4: Low Shear Wet Granulation Tablets Crushing Force, N 200

150

100

50

2% HPC

4% HPC

8% MC

8% PVP

8% PGS

Figure 5: Fluid Bed Granulation Tablets

Lower Compression and Ejection Forces Figure 6 demonstrates the lower ejection forces for HPC relative to PVP, measured at the tablet press. (Reference B.)
Ejection Force, kN 0.4

4% PVP 6% PVP 8% PVP 4% HPC 6% HPC

0.3

0.2

0.1

8% HPC 10 15 20 25 30

Compression Force, kN Figure 6: Fluid Bed Granulation Tablets 3

Modified Release
Cellulose derivatives are often used to modify the release of drugs in tablet and capsule formulations. For tablets, cellulose derivatives provide utility as matrix components and coatings. These systems benefit from ease of manufacture, low cost and predictable in vivo performance. This summary presents formulation guidance for some hydrophilic and hydrophobic systems. HYDROPHILIC MATRIX SYSTEMS Cellulose derivatives such as HPC or HEC are used in hydrophilic matrix systems. High molecular weight grades of KLUCEL HXF or HF HPC or NATROSOL HHX or HX HEC are typically used. As the polymers are exposed to water, they form a gel layer that will retard the release of the active ingredients. Drug release with these systems involve two simultaneous processes: Fickian diffusion and matrix relaxation and erosion. Along with drug load and solubility, polymer swelling, concentration and particle size, pH effects, other excipients and processing variables are important factors when formulating these systems. Drug Solubility The solubility of the drug in hydrophilic tablet matrices is an important factor influencing the choice of polymer to modify the release profile. Figures 1 and 2 show drug solubility effects for systems based on KLUCEL HPC and NATROSOL HEC. KLUCEL is most suitable for highly water-soluble drugs. NATROSOL is appropriate for near zero-order release attainable with sparingly and low solubility drugs. (References A and B.)
% Drug Released 100

% Drug Released 100

80

Phenylpropanolamine (90.9% solubility) Acetaminophen (1.8% solubility) Theophylline (0.8% solubility) Diclofenac Sodium (0.18% solubility, pH 7)

60 40 20 0

8 12 16 Time, hours

20

24

Figure 2: Effect of Drug Solubility on Release From HEC Tablets 40% Drug, 30% NATROSOL 250 HHX HEC, 30% MCC

Robust Processing Options For highly soluble phenylpropanolamine (PPA), the robust processing nature of KLUCEL HXF is shown in Figure 3 with equivalent release profiles in wet granulation, roller compaction and direct compression. (References A and C.)
% Drug Released 100

80 60

40 20

Wet Granulation Roller Compaction Direct Compression 9 12 15

80 60

Time, hours Figure 3: Equivalent Release From HPC Tablets Formulated With Various Processes 20% PPA, 30% KLUCEL HXF HPC, 50% MCC

40 0 20

Phenylpropanolamine (90.9% solubility) Acetaminophen (1.8% solubility) Theophylline (0.8% solubility) 8 12 Time, hours 16 20 24

Figure 1: Effect of Drug Solubility on Release From HPC Tablets 20% Drug, 30% KLUCEL HXF HPC, 50% MCC

Modified Release
KLUCEL Particle Size Again for PPA, Figure 4 shows particle size effects using fine grind HXF with slower drug release relative to regular grind HF. (References A, C, and D.)
% Drug Released 100 80 60 40 20 0

% Drug Released 100 80 60 40 20 0 0 30% KLUCEL HXF HPC 30% KLUCEL HF HPC 8 12 5 10 15 20 25 Time, hours Figure 6: HEC Is Non-ionic; Release From Tablets Is Independent of pH 50% Theophylline, 30% NATROSOL 250HHX HEC, 20% MCC 0.1 N pH 6.8 Buffer HCl

DI Water pH Change

4 Time, Hours

Stability of Release KLUCEL has been studied extensively for one-year stability under various storage conditions (25C, 40C at 80% relative humidity, and 50C). Figure 7 demonstrates the excellent release stability, as compared to the original release profile for PPA. Ongoing studies consider other storage conditions and drugs formulated with KLUCEL and NATROSOL. (Reference E.)
% Drug Released 100 80 60 40

Figure 4: Fine Grind HPC Exhibits Slower Release Than Regular Grind HPC From Tablets 20% PPA, 30% KLUCEL HXF HPC, 50% MCC

Stable to pH Effects KLUCEL HPC or NATROSOL HEC are non-ionic polymers, so that hydration and viscosity development are not influenced by the pH of the dissolution media. Figures 5 and 6 show release profiles for KLUCEL HPC and NATROSOL HEC for changes in pH for theophylline formulations. (Reference B.)
% Drug Released 100 80 60 40 20 0

Original Held for 1 Year at 25C Held for 1 Year at 40C, 80% rh Held for 1 Year at 50C

20 0

pH 1.5 pH 6.8

6 8 Time, hours

10

12

14

Figure 7: HPC Tablets Exhibit Excellent One-Year Stability, Held Under Various Conditions 14% PPA, 25% KLUCEL HXF HPC, 58% Diluent 3 6 Time, hours 9 12

Figure 5: HPC Is Non-ionic; Release From Tablets Is Independent of pH 20% Theophylline, 30% KLUCEL HXF HPC, 50% MCC

Modified Release
HYDROPHOBIC MATRIX AND COMPRESSION COATINGS Hydrophobic matrices, composed of ethylcellulose for instance, do not swell or erode and thereby modify drug release via Fickian diffusion. Direct compression or solvent granulation may be used to incorporate ethylcellulose. Drug actives may alternately be coated in a similar method and incorporated in capsules or other dosage forms. The use of a compression coating will allow a time-delayed pulse release or a time-delayed sustained release, dependent upon the composition of the inner tablet core. Improved Compressible Grade: AQUALON T10 Pharm Ethylcellulose With innovative polymer engineering, Aqualon designed a new grade of ethylcellulose, AQUALON T10 Pharm EC, with optimized compactibility and powder flow. As shown in Figure 8, EC with high ethoxyl content and low viscosity provides improved compaction, without the need for reduction in particle size via micronization. (Low viscosity corresponds to low molecular weight polymer, when dissolved in test solvent.) Detailed studies have included physical, thermal and mechanical characterizations along with powder flow, compaction simulation and molecular modeling. (Reference I). Modified Release Direct Compression Tablets AQUALON T10 Pharm EC can be readily incorporated in stronger direct compression controlled release matrices, eliminating the need for solvents. Figures 8 and 9 show the improvement in crushing strength and retardation of drug release with this improved grade of EC in simple tablet models. (References I and J.)
Crushing Strength, kP 16

% Drug Release 100 80 60 40 20

Ethoxyl, Viscosity, % cps 45.6 7 49.6 94 49.3 80 47.5 10 51.0 9

12 Time, hours

16

20

24

Figure 9: Effect of EC Variables on Drug Release of EC:Acetaminophen (3:1) Tablets

Drug Solubility An understanding of drug load and solubility are important to control drug release. Figure 10 shows the effect of drug solubility in a simple tablet model where Fickian diffusion controls release.
% Drug Released 100
Acetaminophen Solubility, % Drug Phenylpropanolamine 91 Propranolol HCl 5

80 60 40 20

1.8

Theophylline

0.8

Ethoxyl, % 51.0 49.6 49.3 47.5

Viscosity, cps 9 94 80 10

12 Time, hours

16

20

24

Figure 10: Effect of Drug Solubility on Release From AQUALON T10 EC:Drug (3:1) Tablets

12

Effect of Diluent/Filler In these systems, drug release can be modulated by the swellability and solubility of the filler, as shown in Figure 11. Insoluble, non-hydrating dicalcium phosphate provides a slow release profile. Soluble sugars (lactose and mannitol) showed intermediate release behavior. Microcrystalline cellulose (MCC), which is hydrophilic and swellable, but insoluble, displayed the fastest release profile. Soluble excipients are known to act as channeling agents, resulting in increased porosity with ongoing water penetration. Swellable excipients can dramatically increase in volume, causing stress relaxation of the matrix, allowing rapid water ingress.

0 0 5 10 15 20 25 Compression Force, kN Figure 8: Effect of EC Variables on Compactibility of EC:Acetaminophen (3:1) Tablets 6

Modified Release
% Drug Released 100 80

60 40

MCC Mannitol Lactose DicalPhos

than 25% more compactible than the other materials. As shown in Figure 14, this results in increased resistance to water infusion and coating strength, which is critical to achieving prolonged lag times. Tablets compressioncoated with AQUALON T10 EC at 5kN compression force achieved markedly longer lag times than tablets coated at 25 kN with other grades of EC.
% Drug Released 100 80 60

20 0 0

12 16 Time, hours

20

24 40 20 0

T10 EC compressed at 5 kN; all others compressed at 25 kN.

Ethoxyl, Viscosity, % cps 51.0 9.2 49.6 94 49.3 80 47.5 10 45.6 7.1 45.7 83

Figure 11: Diluent Effect on Drug Release From Directly Compressed Model Formulations 25% Acetaminophen, 40% AQUALON T10 EC, 34% Diluent

Pulse Release via Compression Coating A coating of ethylcellulose compressed around a tablet core can delay the delivery of actives for a controlled period of time. The factors that control this function are the coating compactibility and thickness, compression force applied and core swellability. Figure 12 provides a general mechanism for pulse release in these systems with compression force controlling release time, as shown in Figure 13. (Reference K.)
Compressed coat EC 99%, lubricant 1% Immersion in aqueous media

6 8 Time, hours

10

12

Figure 14: Comparison of AQUALON T10 Pharm EC Compression Coat Performance With Other EC Grades Theophylline Model Selected references on modified release are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. Hydrophilic Systems A. Compression and Drug Release Characteristics of Directly Compressible KLUCEL Hydroxypropylcellulose Controlled Release Matrix Systems (Aqualon Pharmaceutical Technology Report PTR-019) B. Versatility of NATROSOL Hydroxyethylcellulose in Controlled Release Matrix Systems (Aqualon Pharmaceutical Technology Report PTR-017) C. KLUCEL Hydroxypropylcellulose Controlled Release Matrix Tablets Prepared by Roll Compaction: Effect of Polymer, Formulation and Processing Variables (Aqualon Pharmaceutical Technology Report PTR-018) D. DA Alderman, U.S. Patent 4,704,285; Sustained release compositions comprising hydroxypropyl cellulose ethers ; granted 11/3/87, expires 11/18/05 (Contact Dow Chemical for further information.) E. One-Year Stability of Sustained-Release Matrix Tablets Formulated with KLUCEL HXF Pharm Hydroxypropylcellulose (Aqualon Technical Information Bulletin VC-565B) F. KLUCEL Pharm Hydroxypropylcellulose Application in a Sustained Release Matrix Capsule Dosage Form (Aqualon Technical Information Bulletin VC-529) G. Lot-to-Lot Variation in KLUCEL HXF Pharm Hydroxypropylcellulose, Effect on Drug Release in Sustained-Release Matrix Tablets (Aqualon Technical Information Bulletin VC-567C) H. NATROSOL 250HX Pharm Hydroxyethylcellulose, Application in a Sustained-Release Matrix Capsule Dosage Form (Aqualon Technical Information Bulletin VC-554) Hydrophobic Matrix and Compression Coatings I. Advanced Structure-Function Properties of Ethylcellulose: Implications For Tablet Compactibility (Aqualon Pharmaceutical Technology Report PTR-021) J. Ethylcellulose In Direct Compression Modified Release Tablets: Impact of Polymer Structure and Formulation Variables (Aqualon Pharmaceutical Technology Report PTR-023) K. Ethylcellulose In Compression Coated Tablets: Implications For Time-Controlled Pulsed-Release Dosage Forms (Aqualon Pharmaceutical Technology Report PTR-022)

Tablet core: with or without swelling agent (0-6% croscarmellose)

Water diffuses through pores of the EC barrier coating. Swelling force/axial relaxation of the inner tablet causes EC coating to open in clamshell manner.

Figure 12: Schematic of Model Compression Coated Pulse Release System % Drug Released 100 80 60 40 20
0 0 4

Compression Force, kN

5 10 25

20 24

8 12 16 Time, hours

Figure 13: Effect of Compression Force on Pulse Release Lag TimeTheophylline Model

Effect of Polymer Grade and Compactibility The compactibility of EC is highly dependent on ethoxyl content and viscosity, with the new grade being greater

Liquid and Semi-Solid Formulations

Solubility and Solution Properties of Aqualon Cellulose Derivatives
Solubility Aqualon Tradename Polymer Charge Anionic Non-Ionic Non-Ionic Non-Ionic Water, Ambient Temp. Soluble Soluble Soluble Insoluble Hot Water Soluble Soluble Insoluble >40C Insoluble Anhydrous Ethanol Insoluble Insoluble Soluble Soluble Other Organic Solvent Insoluble Partial Many Solvents Many Solvents Salt (NaCl) Compatibility Surface Tension, mN m 71.0 66.8 43.6

AQUALON and BLANOSE CMC NATROSOL HEC KLUCEL HPC AQUALON EC

Medium/High High Medium

Relative Trends Among Aqualon Cellulose Derivatives

CMC

HEC

HPC

EC
Increased Organo-Solubility

Increased Water Binding Capacity and Cold Water Solubility

Liquid and semi-solid pharmaceutical dosage forms are important physicochemical systems for medical treatment. A variety of administration routes exist for these dosage forms, including oral, inhalation, dermal, parenteral and mucosal (buccal, vaginal, rectal and ophthalmic) modes. These liquid and semi-solid dosage forms require rheological control and stabilizing excipients as essential additives. With the proper choice of Aqualon water-soluble and organo-soluble excipients, these systems can exhibit (a) increased stability; (b) controlled viscosity to promote delivery; and (c) selected organoleptic properties such as improved mouth-feel. Syrups Syrups are often prepared without sucrose. Viscosity is adjusted by the use of AQUALON or BLANOSE CMC or NATROSOL HEC. Medium or high molecular weight products are generally preferred. Suspension Systems For systems like antacids or X-ray contrast fluids which require stabilization of the suspended solids, AQUALON or BLANOSE CMC is preferred because of the synergistic stabilizing effect of CMC with clays, either from natural or synthetic origin. Liquid Soaps NATROSOL HEC is preferred in the preparation of liquid soaps, because of its good compatibility with surfactant systems. In this case, higher molecular weight grades are recommended for greater efficiency.

Topical Gels Aqueous or hydroalcoholic gels are often used for topical applications. KLUCEL HPC is preferred with hydroalcoholic carriers. Aqueous systems are typically formulated with KLUCEL HPC, NATROSOL HEC, or AQUALON or BLANOSE CMC, depending on the chemical compatibility with other ingredients. Topical Lotions and Creams Emulsified systems provide topical applications ranging from liquid (lotions) to more semi-solid systems (creams). Medium molecular weight NATROSOL HEC is used to modify the rheology and stabilize emulsions. Parenteral and Implant Applications Aqualon has not determined the safety of cellulose derivative products in parenteral or medical implant applications. Formulators need to pursue and ensure the safety of products that may contain cellulose derivatives.
Selected references on liquid and semi-solid formulations are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. A. BLANOSE Sodium CarboxymethylcelluloseAQUALON Sodium CarboxymethylcelluloseStabilizer for Antacids Suspensions (Aqualon Technical Information Bulletin VC-607) B. AQUALON Water-Soluble PolymersSurfactant Compatibility and Recommendations (Aqualon Technical Information Bulletin VC-527A) C. Rheology of AQUALON Water-Soluble Polymers in Solution (Aqualon Technical Information Bulletin VC-453C) D. NATROSOL 250 Pharm Hydroxyethylcellulose in Pharmaceutical Gel Compositions (Aqualon Technical Information Bulletin VC-608)

Tablet Coating
Tensile Strength, MPa Low 15.5 High 89.7 Medium 28.3 High 58.7 Oxygen Transmission, cm3/m2/ atm O2 day Medium 776 Low 18 Low 33 High 3180 Water Vapor Transmission g/m2/day Low 126 Low 228 Medium 360 High 420

Film-Forming Polymer

Elasticity, 10-4/MPa

Elongation, %

KLUCEL EF HPC AQUALON or BLANOSE 7L CMC NATROSOL 250L HEC HPMC 5cps (for comparison)

High 17.5 Low 1.7 High 15.8 Low 3.2

Medium 17.2 Low 5.6 High 33.0 Low 7.6

Aqualon offers a variety of low-viscosity cellulosic polymers, which provide important mechanical, and barrier properties for tablet coating. The table above provides an overall property summary for three AQUALON water-soluble polymers. KLUCEL HPC The flexibility and adhesion of KLUCEL are well known. Due to low surface and interfacial tensions of its solutions, film cracking and monogram bridging can be eliminated. This allows successful formulation of KLUCEL in aqueous film coating alone or to enhance the utility of strong, but brittle, HPMC-based coatings. KLUCEL imparts a variety of benefits: Excellent film adherence to problem tablet substrates such as vitamins; Great reduction in film cracking on the edge of tablets; Improved barrier to water and oxygen transmission; and Elimination of bridging of tablet monograms. In essence, KLUCEL can plasticize HPMC while providing the barrier properties noted. Film formulation guidance is available for KLUCEL alone or in combination with HPMC, applicable to a wide variety of coating equipment and a wide variety of tablet cores. (References A and B.) AQUALON or BLANOSE CMC CMC provides films with high gloss and excellent barrier properties, with low transmission of oxygen and water vapor. Films formed with CMC are strong, but brittle, and need to be plasticized. CMC is compatible with a wide variety of plasticizers, including polyethylene glycol, polypropylene glycol and triacetin. Film formulation information is available. (Reference C.)

NATROSOL HEC As a film-forming highly-elastic polymer, HEC also provides low transmission of oxygen. Because the polymer is non-ionic, it is compatible with a variety of other ingredients, including actives and surfactants. AQUALON EC EC is soluble in a wide range of organic solvents. Its use as a coating for one or more active ingredients in a tablet can prevent them from reacting with other materials or with one another. It can prevent discoloration of easily oxidizable substances such as ascorbic acid. Further, EC can be used in combination with water-soluble polymers to prepare sustained-release coatings of fine particles and tablets, or to provide film coatings with reduced water solubility. For water-based film coatings, EC has been used in latex systems. EC masks the bitter taste of drugs, minimizing the need for added flavoring agents.

Selected references on tablet coating are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. A. KLUCEL EF Pharm Hydroxypropylcellulose, Use in Plasticizer-Free Aqueous Film Coating (Aqualon Technical Information Bulletin VC-598A) B. The Use of KLUCEL Pharm Hydroxypropylcellulose to Increase the Utility of Hydroxypropyl Methylcellulose in Aqueous Film Coating (Aqualon Technical Information Bulletin VC-556C) C. J.L. Johnson, U.S. Patent 4,931,286; High gloss cellulose tablet coating ; granted 6/5/90, expires 4/19/09 D. G. Banker et al, Drug Dev Ind Pharm 1981, 7, 693-716; Evaluation of hydroxypropylcellulose and hydroxypropylmethylcellulose as aqueous-based film coatings E. S.C. Porter and C.H. Bruno, Coating of Pharmaceutical Solid-Dosage Forms in Pharmaceutical Dosage Forms: Tablets, vol 3, 2nd ed, ed. H.A. Lieberman et. al., Marcel Dekker, 1990. 9

Klucel Hydroxypropylcellulose (HPC)

KLUCEL HPC is non-ionic water-soluble cellulose ether, formed by reaction of cellulose with propylene oxide. KLUCEL provides a remarkable set of physical properties for tablet binding, modified release and film coating. It combines organic solvent or aqueous solubility, thermoplasticity and surface activity with aqueous thickening and stabilizing properties characteristic of other water-soluble cellulose polymers available from Aqualon. KLUCEL has a long-standing history of safe and effective use in the pharmaceutical industry. The PHARM grades of KLUCEL HPC comply with the monograph requirements of the National Formulary, the European Pharmacopoeia, and the Japanese Pharmacopoeia. Tablet Coating Low viscosity grades of KLUCEL impart good flexibility and adhesion to films while providing a good barrier to water and oxygen transmission. Grades EF and LF are commonly used.

Physical and Chemical Properties

Non-ionic, pH insensitive cellulose ether Soluble in many polar organic solvents and in water below 38C, but insoluble in water above 45C Tough, yet ductile, thermoplastic polymer for compression molding or extrusion Film forming, yielding flexibility and adhesion without plasticizers due to low surface and interfacial tensions of solutions Thickening and stabilizing properties similar to other water-soluble cellulose polymers Compatible with a variety of surfactants: anionic, cationic and amphoteric Available in a wide range of viscosities and molecular weights KLUCEL HPC PHARM Grade HF MF GF JF LF EF Aqueous Solution Viscosity: Typical Brookfield at Concentration Shown, mPas 1,500-3000 4,000-6,500 150-400 150-400 75-150 300-600 at 1% at 2% at 2% at 5% at 5% at 10% Molecular Weight (weight averaged) 1,150,000 850,000 370,000 140,000 95,000 80,000

Common Applications and Product Grades

Tablet Binding for Immediate Release Low viscosity grades of KLUCEL yield unmatched tablet hardness and friability, at typical use levels of 2 to 8%, in a wide variety of processing options. Wet Granulation (high or low shear or fluid bed) Grades EF and LF with regular particle size are often used in granulating solutions. Alternately, grade EXF, with fine particle size, can be added dry to other ingredients, followed by granulation with water or solvent. Direct Compression or Dry Granulation (roller compaction or slugging) Grade EXF with fine particle size is highly recommended. Modified Release High viscosity grades of KLUCEL provide effective diffusion-limiting matrix systems at use levels of 15-40%, most suited for active ingredients with higher water solubility. Grades HXF with fine particle size or HF with regular particle size are commonly used.

10

Klucel Hydroxypropylcellulose (HPC)

Selected references on the premier performance of KLUCEL HPC are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. Tablet Binding for Immediate Release A. Effect of KLUCEL EF and EXF Hydroxypropylcellulose as Granulating Agents in a Medium-Dose Acetaminophen Tablet Formulation (Aqualon Technical Information Bulletin VC-559B) B. Effect of KLUCEL EF and EXF Hydroxypropylcellulose as Granulating Agents in Low-Dose Hydrochlorothiazide Tablet Formulation (Aqualon Technical Information Bulletin VC-572A) C. Lot-to-Lot Uniformity of KLUCEL EXF Hydroxypropylcellulose as a Granulating Agent (Aqualon Technical Information Bulletin VC-588A) D. Assessment of Low-Viscosity Polymers as Direct Compression Binders in a Model System (Aqualon Pharmaceutical Technology Report PTR-005) E. Correlating the Ejection Force of Tablets with the Toughness of Binders in the Solid Dosage Forms (Aqualon Pharmaceutical Technology Report PTR-009) F. Evaluation of Low-Viscosity Polymers in a Model High-Dose, Acetaminophen Formulation (Aqualon Pharmaceutical Technology Report PTR-011) G. G.W. Skinner et al, Drug Dev Ind Pharm 1999 Oct; 25(10):1121-8; The evaluation of fine-particle hydroxypropylcellulose as a roller compaction binder in pharmaceutical applications Modified Release H. KLUCEL Hydroxypropylcellulose Application in a Sustained Release Matrix Capsule Dosage Form (Aqualon Technical Information Bulletin VC-529) I. One-Year Stability of Sustained-Release Matrix Tablets Formulated with KLUCEL HXF Pharm Hydroxypropylcellulose (Aqualon Technical Information Bulletin VC-565B) J. Lot-to-Lot Variation in KLUCEL HXF Pharm Hydroxypropylcellulose, Effect on Drug Release in Sustained-Release Matrix Tablets (Aqualon Technical Information Bulletin VC-567C) K. D.A. Alderman, U.S. Patent 4,704,285; Sustained release compositions comprising hydroxypropyl cellulose ethers; granted 11/3/87, expires 11/18/05 (Contact Dow Chemical for further information.) L. D.Y. Lee and C.M. Chen, U.S. Patent 6,103,263, granted 8/15/00, expires 11/17/14; Delayed pulse release hydrogel matrix tablet Tablet Coating M. G. Banker et al, Drug Dev Ind Pharm 1981, 7, 693-716; Evaluation of hydroxypropylcellulose and hydroxypropylmethylcellulose as aqueous-based film coatings N. The Use of KLUCEL Pharm Hydroxypropylcellulose to Increase the Utility of Hydroxypropyl Methylcellulose in Aqueous Film Coating (Aqualon Technical Information Bulletin VC-556C) O. KLUCEL EF Pharm Hydroxypropylcellulose, Use in Plasticizer-Free Aqueous Film Coating (Aqualon Technical Information Bulletin VC-598A) Physical, Chemical, Toxicological and Microbiological Properties P. KLUCEL Hydroxypropylcellulose, Pharm Grade for Pharmaceutical Uses (Aqualon Product Data Bulletin 494-8) Q. KLUCEL Hydroxypropylcellulose Physical and Chemical Properties (Aqualon Product Booklet 250-2F) R. KLUCEL Hydroxypropylcellulose, Techniques for Dispersion and Dissolution (Aqualon Technical Information Bulletin VC-516A) S. KLUCEL Hydroxypropylcellulose Summary of Toxicological Investigations (Aqualon Toxicological Data Bulletin T-122E) T. KLUCEL HydroxypropylcelluloseMicrobiological Information (Aqualon Product Data Bulletin 4083) U. C. Alvarez-Lorenzo et al, Drug Dev Ind Pharm 2000, 26(1),13-20; The Stability of Theophylline Tablets with a Hydroxypropylcellulose Matrix

11

Aqualon and Blanose Sodium Carboxymethylcellulose (CMC)

CMC is an anionic, water-soluble polymer derived from cellulose reacted with sodium monochloroacetate. CMC is a common thickener, binder, stabilizer, suspending agent, and rheology control reagent. AQUALON CMC and BLANOSE CMC are products typically used in the United States and Europe, respectively. AQUALON CMC grades designated P or PH are compliant with the monograph requirements of the United States Pharmacopeia / National Formulary. BLANOSE CMC grades designated P or PH are compliant with the monograph requirements of the European Pharmacopoeia and the United States Pharmacopeia / National Formulary. Aqualon can provide CMC types with custom specifications upon request with advance planning. Also, with advance request, and subject to lot selection and testing fees, certain AQUALON CMC grades may also be tested to meet the monograph requirements of the European Pharmacopoeia and the Japanese Pharmacopoeia. With similar conditions, certain BLANOSE CMC grades may also be tested to meet the monograph requirements of the Japanese Pharmacopoeia. Common Applications Ointments, Creams, and Lotions Stabilizer, thickener, film-former Jellies and Salves Thickener, gelling agent, protective colloid, film-former Syrups and Suspensions Thickener, suspending aid Bulk Laxatives Physiologically inert, high water-binding capacity Mucoadhesives Absorbency Sustained Release Thickener, diffusion barrier Tablet Coating Film-former Physical and Chemical Properties and Common Product Grades Soluble in cold or hot water, insoluble in organic solvents, compatible with water/alcohol systems Film forming, imparting low water and oxygen transmission to coatings Wide range of substitution: The degree of substitution is a measurement of the number of carboxymethyl groups present on the cellulose backbone. Lower substitution (7 types) provide thixotropy Higher substitution (9 and 12 types) provide little or no thixotropy where smoother solutions without structure are required Available in a wide range of viscosities and substitutions, shown on page 13. A variety of particle size subtypes are also available.

12

Aqualon and Blanose Sodium Carboxymethylcellulose (CMC)

AQUALON CMC Typical Viscosity, cps High (1% concentration) 1,500-3,000 1,000-2,800 Medium (2% concentration) 1,500-3,100 800-3,100 400-800 300-800 Low (2% concentration) 25-50 Extra Low (4% concentration) 50-200 7L2P Options for particle size: coarse (C), regular or finely (X) ground grades S-types provide smooth solutions, based on uniform substitution O-types provide solubility and viscosity stability on storage in low pH media 7LF PH 7MF PH 7M8SF PH 9M8F PH 7HF PH 7H3SF PH 7HOF PH 0.7 Degree of Substitution 0.9 1.2 BLANOSE CMC Typical Viscosity, mPa.s High (1% concentration) 2,500-4,500 1,500-2,500 1,000-2,800 7H4F PH 7HF PH 7H3SF PH 7HOF PH 9H4F PH 0.7 Degree of Substitution 0.9 1.2

9M31F PH 12M31P 12M8P

Medium (2% concentration) 1,500-3,100 7M31F PH 9M31F PH 12M31P 200-800 7M8SF PH 12M8P 400-600 7MF PH Low (2% concentration) 50-100 25-50 7M1F PH 7LF PH

Selected references on AQUALON or BLANOSE CMC are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. Solution Thickening, Stabilizing and Suspending Agent A. AQUALON Cellulose DerivativesExcipients for Liquid or SemiSolid Pharmaceutical Dosage Forms (Aqualon Booklet 250-48) B. BLANOSE Sodium CarboxymethylcelluloseAQUALON Sodium CarboxymethylcelluloseStabilizer for Antacid Suspensions (Aqualon Technical Information Bulletin VC-607) C. AQUALON Water-Soluble Polymers Surfactant Compatibility and Recommendations (Aqualon Technical Information Bulletin VC-527A) Modified Release D. AQUALON Cellulose GumUtility in the Formulation of Sustained-Release Matrix Tablets (Aqualon Information Bulletin VC-542A)

Tablet Coating E. J.L. Johnson, U.S. Patent 4,931,286; High gloss cellulose tablet coating ; granted 6/5/90, expires 4/19/09 Physical, Chemical, Toxicological and Microbiological Properties F. AQUALON Sodium Carboxymethylcellulose Physical and Chemical Properties (Aqualon Product Booklet 250-10H) G. AQUALON Sodium Carboxymethylcellulose Product Specifications (Aqualon Product Data Bulletin 4116-4) H. AQUALON Cellulose Gum, Dispersion and Dissolution (Aqualon Technical Information Bulletin VC-524A) I. Rheology of AQUALON Water-Soluble Polymers in Solution (Aqualon Technical Information Bulletin VC-453C) J. AQUALON Cellulose Gum (Sodium Carboxymethylcellulose) Summary of Toxicological Investigations (Aqualon Toxicological Data Bulletin T-123D) K. AQUALON Cellulose GumMicrobiological Information (Aqualon Product Data Bulletin 4016) L. Regulatory Status of AQUALON Cellulose Gum for Use in Foods (Aqualon Technical Information Bulletin VC-541A)

13

Aqualon Ethylcellulose (EC)

AQUALON EC is the non-ionic ethyl ether of cellulose, soluble in a wide range of organic solvents. Typically, ethylcellulose is used as a non-swellable, insoluble component in matrix or coating systems. When watersoluble binders cannot be used in dosage processing because of water sensitivity of the active ingredient, ethylcellulose is often chosen. The PHARM grades of AQUALON EC are compliant with the monograph requirements of the United States Pharmacopeia/ National Formulary and the European Pharmacopeia. Ethylcellulose can be used to coat one or more active ingredients of a tablet to prevent them from reacting with other materials or with one another. It can prevent discoloration of easily oxidizable substances such as ascorbic acid, allowing granulations for easily compressed tablets and other dosage forms. Ethylcellulose can be used on its own or in combination with water-soluble polymers to prepare sustained release film coatings that are frequently used for the coating of micro-particles, pellets and tablets. Improved Compressible Grade: AQUALON T10 EC With innovative polymer engineering, Aqualon designed a new grade of ethylcellulose, AQUALON T10 EC, with optimized compactibility and powder flow. As shown in Figure 1, EC with high ethoxyl content and low viscosity provides improved compaction, without the need for reduction in particle size via micronization. (Low viscosity corresponds to low molecular weight polymer, when dissolved in test solvent.) Detailed studies have included physical, thermal and mechanical characterizations along with powder flow, compaction simulation and molecular modeling. (Reference A.) Powder flow characterizations are shown in the table on the next page. Common Applications Microencapsulation Stabilize against active interactions, hydrolysis and oxidation and/or retard release of active ingredients Flavor Masking Improved taste through suppression of strong flavors or bitter taste of drugs, minimizing the need for added flavoring agents. Tablet Binder Plastic flow, suitable for direct compression, injection molding and melt extrusion Modified Release Direct Compression Tablets AQUALON T10 EC can be readily incorporated in stronger direct compression controlled release matrices, eliminating the need for solvents. Figures 2 and 3 show the improvement in crushing strength and retardation of drug release with this improved grade of EC. (References A and B.) Tablet Coating Impart sustained release to film coatings Modified Release Compression Coating AQUALON T10 EC may be used to coat tablet cores forming a non-swelling, insoluble diffusion barrier to achieve either sustained release or time-controlled, delayed release profiles. (Reference C.) Solution Thickening Impart thickening for non-aqueous systems
Crushing Strength, kP 16 Crushing Strength, kP 18.8

Ethoxyl, % 51.0 49.6 49.3 47.5

Viscosity, cps 9 94 80 10

12

4 6.3 51 10 % Ethoxyl 45 190 Figure 1: High Ethoxyl Content and Low Viscosity Optimization of Crushing Strength of Pure Polymer EC Compacts Viscosity, cps 0 0

10

15

20

25

Compression Force, kN Figure 2: Effect of EC Variables on Compactibility of EC:Acetaminophen (3:1) Tablets

14

Aqualon Ethylcellulose (EC)

% Drug Release 100 80 60 40 20

Ethoxyl, Viscosity, % cps 45.6 7 49.6 94 49.3 80 47.5 10 51.0 9

Comparison of Flow Properties AQUALON T10 EC High Ethoxyl, Low Viscosity Micronized EC* 25 36 12% 11 g/sec 4.5 sec 51 51 14% <1 g/min 8.7 sec

Test Parameter Angle of Repose Angle of Slide Compressibility Index Flow rate (9 mm orifice)

12 Time, hours

16

20

24

Mean Time to Avalanche

Figure 3: Effect of EC Variables on Drug Release of EC:Acetaminophen (3:1) Tablets

* Ethocel Standard FP 10 Premium ethylcellulose is a registered trademark of The Dow Company, Midland Michigan, U.S.A.

Physical and Chemical Properties Non-ionic, pH insensitive cellulose ether Soluble in many polar organic solvents; insoluble in water. Tough, yet ductile thermoplastic polymer for compression molding or extrusion Film forming, yielding flexible films over a wide range of temperatures Available in a wide range of viscosities and two ethoxyl contents: Typical Viscosity, cps (5% solution of 80/20 mixture of toluene/ethanol)

Selected references on AQUALON EC are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. Improved Compressible Grade: AQUALON T10 Pharm EC A. Advanced Structure-Function Properties of Ethylcellulose: Implications for Tablet Compactibility (Aqualon Pharmaceutical Technology Report PTR-021) B. Ethylcellulose In Direct Compression Modified Release Tablets: Impact of Polymer Structure and Formulation Variables (Aqualon Pharmaceutical Technology Report PTR-023) C. Ethylcellulose In Compression Coated Tablets: Implications for Time-Controlled Pulsed-Release Dosage Forms (Aqualon Pharmaceutical Technology Report PTR-022) Flavor Masking D. AQUALON Ethylcellulose for Use in Pharmaceuticals and Flavorings to Improve Their Organoleptic Properties (Aqualon Product Marketing News Bulletin M-318B) Physical, Chemical and Microbiological Properties E. AQUALON Ethylcellulose (EC) Physical and Chemical Properties (Aqualon Product Booklet 250-42A) F . AQUALON Pharm Ethylcellulose for Food and Pharmaceutical Applications (Aqualon Product Data Bulletin 4176-1) G. AQUALON EthylcelluloseA Versatile Film-Forming Cellulose Ether (Aqualon Product Data Bulletin 452-7) H. AQUALON EthylcelluloseMicrobiological Information (Aqualon Product Data Bulletin 4150)

Type

High Ethoxyl Substitution (49.6-51.0%) T10 8-11

Standard Ethoxyl Substitution (48.0-49.5%) N7 N10 N14 N22 N50 N100 6-8 8-11 12-16 18-24 40-52 80-105

15

Natrosol Hydroxyethylcellulose (HEC)

NATROSOL HEC is a non-ionic water-soluble cellulose ether, formed by reaction of cellulose with ethylene oxide. It is used as (a) a modified release tablet matrix, (b) a film former, and (c) a thickener, stabilizer and suspending agent for oral and topical applications when a non-ionic material is desired. NATROSOL is easily dispersed in cold or hot water to give solutions of varying viscosities and desired properties, yet it is insoluble in organic solvents. The PHARM grades of NATROSOL HEC comply with the monograph requirements of the National Formulary and the European Pharmacopoeia. Common Applications and Product Grades
Solution Thickening, Stabilizing, and Suspending Agent Medium or high viscosity grades of NATROSOL are used to control rheology, providing thickening and pseudoplasticity, and to stabilize emulsions with high salt tolerance and surfactant compatibility. Clear solutions and gels may be formulated. Higher viscosity grades yield greater thickening efficiency. Grades 250 M, H, HX, and HHX are typically chosen for oral and topical liquid and gel formulations. Aqueous Solution Viscosity: Typical Brookfield at Molecular Weight Concentration (estimated from Shown, mPas intrinsic viscosity) 3,500-5,500 1,500-2,500 1,500-2,500 4,500-6,500 250-400 75-150 at 1% at 1% at 1% at 2% at 2% at 5% 1,300,000 1,000,000 1,000,000 720,000 300,000 90,000 Tablet Coating Low viscosity grades of NATROSOL impart flexibility to films while providing a good barrier to water and oxygen transmission. Grade 250 L is the low viscosity grade of choice. Physical and Chemical Properties Non-ionic, pH insensitive cellulose ether High solubility in cold or hot water with rapid hydration; insoluble in organic solvents High salt tolerance and surfactant compatibility due to non-ionic nature Film forming, imparting flexibility to coatings Available in a wide range of viscosities and molecular weights
Selected references on the premier performance of NATROSOL HEC are available on the Aqualon website at www.aqualon.com or by contacting one of our worldwide offices shown in this brochure. Modified Release A. NATROSOL 250HX Pharm Hydroxyethylcellulose, Application in a Sustained-Release Matrix Capsule Dosage Form (Aqualon Technical Information Bulletin VC-554B) B. Versatility of NATROSOL Hydroxyethylcellulose in Controlled Release Matrix Systems (Aqualon Pharmaceutical Technology Report PTR-017) Solution Thickening, Stabilizing, and Suspending Agent C. AQUALON Cellulose DerivativesExcipients for Liquid or Semi-Solid Pharmaceutical Dosage Forms (Aqualon Booklet 250-48) D. NATROSOL 250 Pharm Hydroxyethylcellulose in Pharmaceutical Gel Compositions (Aqualon Technical Information Bulletin VC-608) E. AQUALON Water-Soluble Polymers Surfactant Compatibility and Recommendations (Aqualon Technical Information Bulletin VC-527A) Physical, Chemical, Toxicological and Microbiological Properties F. NATROSOL HydroxyethylcelluloseA Nonionic Water Soluble PolymerPhysical and Chemical Properties (Aqualon Product Booklet 250-11G) G. NATROSOL Hydroxyethylcellulose, Techniques for Dispersion and Dissolution (Aqualon Technical Information Bulletin VC-515B) H. Rheology of AQUALON Water-Soluble Polymers in Solution (Aqualon Technical Information Bulletin VC-453C) I. NATROSOL Hydroxyethylcellulose Summary of Toxicological Investigations (Aqualon Toxicological Data Bulletin T-101G) J. NATROSOL HydroxyethylcelluloseMicrobiological Information (Aqualon Product Data Bulletin 4082) K. NATROSOL 250 HydroxyethylcelluloseA Nonionic Water-Soluble Cellulose Ether (Aqualon Product Data Bulletin 4146) L. NATROSOL Hydroxyethylcellulose for Use in PharmaceuticalsA Position Statement (Aqualon Product Data Bulletin 4059-3)

NATROSOL HEC PHARM Grade HHX HX H M G L

Modified Release Higher viscosity grades of NATROSOL provide effective diffusion-limiting matrix systems at use levels of 15-40%, most suited for active ingredients with low water solubility, where near zero-order release is desired. Grades 250 HHX, HX, H, M, and G are preferred.

16

www.aqualon.com
provides additional literature and sample ordering online.

Aqualon 1313 North Market Street Wilmington, DE 19894-0001 Tel: (800) 345-0447 Fax: (302) 992-7287 Hercules GmbH Paul-Thomas-Strasse 56 Postfach 13 01 25 D-40599 Dsseldorf Germany Tel: +31 70-307 1061 Fax: +31 70-319 1187 Hercules Chemicals Singapore Pte. Ltd. 200 Pandan Loop #07-01 Pantech 21 Singapore 128388 Tel.: +65 6775 5366 Fax: +65 6776 9690 Hercules Mexico, S.A. de C.V Saltillo No 19, 7 piso Col. Condesa C.P. 06100 Mexico City, Mexico Tel.: 525-211-0111 Fax: 525-212-0883 www.aqualon.com
A Business Unit of Hercules Incorporated

Hercules Incorporated and its Aqualon subsidiary (together referred to as Hercules) believes that all information provided with respect to its products is accurate at the time such information is provided. Unless otherwise agreed, Hercules makes no express, implied, or other representation, warranty, or guarantee concerning such information or the handling, use, or application of its products, whether alone or in combination with other products, except that its products are of Hercules standard quality. Users of Hercules products are advised to perform their own tests to determine the safety and suitability of each such product or product combination. Users are urged to read and understand the Material Safety Data Sheet (MSDS) and to abide by all use and safety recommendations detailed therein and on all product labeling. Hercules does not recommend the use of its products in any manner which would violate any patent or intellectual property rights. Unless otherwise agreed, the purchasers of Hercules products assume all responsibility and liability for all loss or damage arising from the improper handling or use of our products. This disclaimer supersedes any prior or different disclaimers for this product.

250-49B 8-06